WO2008112407 discloses anti-tumour compounds, and also discloses processes for their preparation, pharmaceutical compositions containing them as active ingredients, methods for treating the disease states associated with angiogenesis, such as tumours associated with protein tyrosine kinases. The above-mentioned compounds can inhibit the activities of tyrosine kinases such as VEGFr, EGFr and PDGF, and they may also be irreversible inhibitors of tyrosine kinases. Its Description also discloses treatment regimens for said spiro substituted compounds and the daily oral administration dosage is preferably 0.01-200 mg/Kg. The daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections and use of infusion technique is preferably 0.01-200 mg/Kg. The daily rectal administration dosage is preferably 0.01-200 mg/Kg. The daily vaginal administration dosage is preferably 0.01-200 mg/Kg. The daily topical administration dosage is preferably 0.01-200 mg, administered 1-4 times daily. The preferred transdermal concentration is that required to maintain a daily dose of 0.01-200 mg/Kg. The daily inhalation dosage is preferably 0.01-200 mg/Kg. The Examples therein discloses formulations of a part of the spiro substituted compounds, including capsules and liquid formulations. The amount of the active ingredients in the capsules is 100 mg.
Chinese patent application CN102344438A discloses Forms A, B and C crystal of the compound of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine dihydrochloride, and the preparation method, and also discloses a pharmaceutical composition comprising the crystal forms. And it points out that the pharmaceutical compositions suitable for oral administration includes tablets, capsules, dusts, granulates, drip pills, pastes, powders, tinctures and the like, and tablets and capsules are preferred. Among them, the tablets can be common tablets, dispersible tablets, effervescent tablets, sustained release tablets, controlled release tablets or enteric coated tablets, and the capsules can be common capsules, sustained release capsules, controlled release capsules or enteric coated capsules. They can be prepared with well-known routine pharmaceutical excipients in the art by conventional methods. The amount of active substances in one unit formulation of oral tablets and capsules should vary depend on treatment conditions of patients and specific administration route. For example, the unit formulation for oral administration can conveniently contain 1 mg-100 mg of active substances, preferably 3 mg-30 mg of active substances.
Tyrosine kinases are a group of enzymes that catalyze phosphorylation of tyrosine residues in proteins, and they play an important role in the cellular signal transduction. Meanwhile, they involve in regulation, signal transmission and development of normal cells, and they are also closely related to proliferation, differentiation, migration and apoptosis of tumour cells. Many receptor tyrosine kinases are correlated with the formation of tumours, and according to the different structures of the extracellular domain, they can be classified as epidermal growth factor receptor, platelet-derived growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and so on. Currently, tyrosine kinase inhibitors marketed in China are imatinib mesylate, sunitinib malate, erlotinib hydrochloride, dasatinib, lapatinib mesylate, nilotinib, gefitinib and icotinib hydrochloride.